Serelaxin is a case study in the distance between a well-characterised mechanism and a clinical endpoint. Relaxin-2, the peptide it reproduces, has a mechanism that reads as almost tailor-made for acute heart failure: it dilates blood vessels, raises arterial compliance, reduces vascular resistance and works against the fibrotic remodelling that drives cardiac and renal injury. Two Phase 3 programmes later, that mechanism has still not translated into a licensed therapy. The record is worth setting out precisely.
What relaxin-2 is
Relaxin-2 is an endogenous peptide hormone of the relaxin family. It is a two-chain structure — an A-chain and a B-chain linked by disulfide bonds — and it is the principal ligand for the relaxin family peptide receptor 1 (RXFP1) [5]. Its physiological profile is best known from pregnancy, where circulating concentrations rise to support the substantial cardiovascular and renal adaptations that pregnancy demands. It is present at lower levels in non-pregnant adults of both sexes, where it is increasingly studied as a vasoactive and antifibrotic signalling molecule [6].
The RXFP1 receptor
RXFP1 is a G-protein-coupled receptor with an unusually complex activation mechanism; binding recruits adenylyl cyclase and raises cyclic AMP, and downstream signalling engages PI3K/Akt and nitric-oxide pathways [4][5]. Expression is prominent in the endothelium of resistance vessels, which is consistent with the vasodilatory phenotype seen when relaxin-2 is applied experimentally. A key feature discussed in the pharmacology literature is how readily the system is altered in disease: RXFP1 expression is reported to fall in fibrotic tissue, and the receptor's splicing variants and dimerisation add further layers of regulation [4].
The mechanism that made it a candidate
Across preclinical models, relaxin-2 has been associated with several effects that, taken together, form a plausible cardiovascular rationale [6]:
- Vasodilation and haemodynamics — endothelium-dependent relaxation and reduced vascular resistance.
- Antifibrotic remodelling — regulation of extracellular-matrix turnover and inhibition of profibrotic TGF-beta signalling in cardiac fibroblasts.
- Anti-inflammatory and anti-oxidant effects — reduced markers of inflammation, apoptosis and oxidative stress in experimental models.
- Organ protection — reduced biochemical markers of cardiac, renal and hepatic injury in the RELAX-AHF programme [2].
These properties are why serelaxin — then designated RLX030 — advanced into a large clinical-development programme.
The clinical record
Pre-RELAX-AHF and RELAX-AHF
The Phase 2 Pre-RELAX-AHF study and the Phase 3 RELAX-AHF study were international, multicentre, double-blind, placebo-controlled trials in which patients hospitalised for acute heart failure were randomised to intravenous placebo or serelaxin within 16 hours of presentation [2]. In RELAX-AHF, serelaxin met one of its two primary dyspnoea endpoints, with the effect driven almost entirely by a reduction in worsening heart failure, and both all-cause and cardiovascular mortality at 180 days were lower than placebo in that trial. Those secondary findings generated considerable interest alongside the biomarker improvements seen in cardiac, renal and hepatic injury markers [2].
RELAX-AHF-2
RELAX-AHF-2 was the confirmatory test: a multicentre trial enrolling approximately 6,600 patients hospitalised for acute heart failure, randomised within 16 hours to a 48-hour intravenous infusion of serelaxin (30 micrograms/kg/day) or placebo on top of standard care, with two independently powered primary endpoints — cardiovascular death at 180 days and worsening heart failure through day five [1][3].
The results, presented in 2017, were negative on both. Cardiovascular mortality at 180 days was 8.7% with serelaxin versus 8.9% with placebo (p = 0.77), and worsening heart failure at five days was 6.9% versus 7.7% (p = 0.19) [3][7]. The trial did not demonstrate superiority of serelaxin over placebo for either primary endpoint, and Novartis subsequently confirmed the programme would not proceed toward regulatory filing on that basis [3].
What the miss does and does not tell us
A negative pivotal trial does not invalidate the underlying biology; it establishes that 48 hours of intravenous serelaxin, in that population and at that dose, did not move two hard clinical endpoints. A mechanistic programme with a strong preclinical column and a failed confirmatory trial is a familiar pattern, and it is the reason evidence grading focuses on human outcomes rather than on plausibility. Later post-hoc analyses have explored comorbidity clustering within RELAX-AHF-2, but these are hypothesis-generating and cannot rescue the primary result [3].
Evidence position
On the four-tier Peptide Data scale, the human clinical evidence for serelaxin in acute heart failure is best characterised as Limited: one positive Phase 3 with a mechanistic and mortality signal, followed by a large confirmatory Phase 3 that missed both primary endpoints. The preclinical literature on relaxin-2 signalling and RXFP1 is comparatively deep and coherent, but a deep preclinical column beside a negative pivotal result is precisely the situation the grading system is designed to make visible, not to smooth over.
UK regulatory position
Serelaxin holds no marketing authorisation from the MHRA and is not available for prescribing in the UK [3]. As an unapproved investigational peptide it falls outside routine supply, and — as with any research peptide — material offered for sale outside an authorised clinical-trial setting should be treated with significant caution. UK law that governs medicines supply here is the framework of the Medicines Act 1968 and the Human Medicines Regulations 2012, administered by the MHRA; nothing in this explainer is a route to lawful human supply.
This article describes research findings and the regulatory record only. Peptide Data does not provide consumption, dosing or self-administration guidance, and nothing here should be read as advice for human use. Peptides are discussed strictly as research compounds.
References
- Teerlink JR, et al. Serelaxin in acute heart failure: rationale and design of the RELAX-AHF-2 study. European Journal of Heart Failure, 2017. PubMed 28452195.
- Teerlink JR, et al. Effect of serelaxin on cardiac, renal and hepatic biomarkers in acute heart failure (Pre-RELAX-AHF and RELAX-AHF). JACC, 2013. Cited in the RELAX-AHF programme literature.
- American College of Cardiology. RELAXin in Acute Heart Failure-2 (RELAX-AHF-2). Clinical trial summary, 2017.
- The relaxin family peptide receptor 1 (RXFP1): an emerging player in human health and disease. PMC 7196478.
- Bathgate RAD, et al. Relaxin family peptides and their receptors. Physiological Reviews, 2013.
- Relaxin-2 as a potential biomarker in cardiovascular diseases. PMC 9317583.
- Novartis. Update on Phase III study of RLX030 (serelaxin) in patients with acute heart failure. Media release, 2017.
This article is AI-researched and editorially reviewed. It is provided for research and educational purposes only and is not medical advice. Research peptides are not licensed for human consumption in the UK.